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According to the novel, Gumb was born in California on October 25, 1949, and abandoned by his mother — an alcoholicprostitute who misspelled "James" on his birth certificate — and then taken into foster care at age two. The film's screenplay omits Gumb's backstory, but does imply that he had a traumatic childhood. In the movie, Lecter summarizes Gumb's life thus: "Billy was not born a criminal, but made one by years of systematic abuse."

The novel goes on to tell of Gumb living in foster homes until the age of 10 before getting adopted by his grandparents, who became his first victims. The story then puts him in Tulare Vocational Rehabilitation, a psychiatric hospital where he learns to be a tailor. Later, Gumb has a relationship with Benjamin Raspail. After Raspail left him, he kills Raspail's new lover, Klaus, and flays him.[1]

Both the novel and film tell of Gumb wanting to become a woman but being too disturbed to qualify for gender reassignment surgery. He kills women so he can skin them and create a "woman suit" for himself. He is described as not really transgender, but merely believing himself to be because he "hates his own identity".

Gumb's modus operandi is to approach a woman, pretending to be injured and asking for help, then knocking her out in a surprise attack and kidnapping her. He takes her to his house and leaves her in a well in his basement, where he starves her until her skin is loose enough to easily remove. In the first three cases, he leads the victims upstairs, slips nooses around their necks and pushes them from the stairs, strangling them. He then skins parts of their body (a different section on each victim), and then dumps each body into a different river, destroying any trace evidence. This MO caused the homicide squad to nickname him Buffalo Bill (Buffalo Bill's Wild West show typically claimed that Buffalo Bill Cody had scalped a Cheyenne warrior). One officer quipped it was because he "skins his humps." [2] In the case of Gumb's first victim, Fredrica Bimmel, he weighed down her body, so she ends up being the third victim found. In the case of the fourth victim, he shoots her instead of strangling her, then inserts a Death's-head Hawkmoth in her throat, and dumps the body.

At the start of the novel, Gumb has already murdered five women. FBI Director Jack Crawford assigns gifted trainee Clarice Starling to question incarcerated serial killer Hannibal Lecter about the case. (Lecter had met Gumb while treating Raspail.) When Gumb kidnaps Catherine Martin, the daughter of U.S. Senator Ruth Martin, Lecter offers to give Starling a psychological profile of the killer in return for a transfer to a federal institution; this profile is mostly made up of cryptic clues designed to help Starling figure it out for herself.

Starling eventually deduces from Lecter's riddles that Gumb knew his first victim, Bimmel, and goes to Bimmel's hometown of Belvedere, Ohio to gather information. By this time, Crawford has already found out the killer's true identity and gone with a SWAT team to his house to arrest him, but they find that it is only a business address. Meanwhile, Starling goes to the home of Bimmel's employer, Mrs. Lippman, only to find Gumb — calling himself "Jack Gordon" — living there. (Gumb had murdered Mrs. Lippman earlier.) When Starling sees a Death's head moth flutter by, she realizes she has found her man and orders him to surrender. Gumb flees into the basement and stalks her with a revolver and night vision goggles. Just as he is about to shoot Starling, she hears him behind her, turns around and opens fire, killing him.

Marjorie Garber, author of Vested Interests: Cross-Dressing and Cultural Anxiety, asserts that despite the book and the film indicating that Buffalo Bill merely believes himself to be transsexual, they still imply negative connotations about transsexualism. Garber says, "Harris's book manifests its cultural anxiety through a kind of baroque bravado of plot," and calls the book "a fable of gender dysphoria gone spectacularly awry".[5]

Barbara Creed, writing in Screening the Male: Exploring Masculinities in the Hollywood Cinema, says that Buffalo Bill wants to become a woman "presumably because he sees femininity as a more desirable state, possibly a superior one". For Buffalo Bill, the woman is "[a] totem animal". Not only does he want to wear women's skin, he wants to become a woman; he dresses in women's clothes and tucks his penis behind his legs to appear female. Creed writes, "To experience a rebirth as woman, Buffalo Bill must wear the skin of woman not just to experience a physical transformation but also to acquire the power of transformation associated with woman's ability to give birth." Buffalo Bill wears the skin of his totem animal to assume its power.[6]

Judith Halberstam, author of Skin Shows: Gothic Horror and the Technology of Monsters, writes, "The cause for Buffalo Bill's extreme violence against women lies not in his gender confusion or his sexual orientation but in his humanist presumption that his sex and his gender and his orientation must all match-up to a mythic norm of white heterosexual masculinity." Halberstam says Buffalo Bill symbolizes a lack of ease with one's skin. She writes that the character is also a combination of Victor Frankenstein and his monster in how he is the creator gathering body parts and experimenting with his own body. Halberstam writes, "He does not understand gender as inherent, innate; he reads it only as a surface effect, a representation, an external attribute engineered into identity." Buffalo Bill challenges "the interiority of gender" by taking skin and remaking it into a costume.[7]

The film adaptation of Silence of the Lambs was criticized by some gay rights groups for its portrayal of the psychopathic Gumb as bisexual and transgender.[8] A Johns Hopkins sex-reassignment surgeon, present in the book but not the film (his scene was deleted and is found in bonus materials on the DVD), protests exactly the same thing; FBI Director Jack Crawford pacifies him by repeating that Gumb is not in fact transsexual, but merely believes himself to be. In the film, a similar scene is shown with Starling and Lecter in the same roles as the surgeon and Crawford, respectively. In the director's commentary for the 1991 film, director Jonathan Demme draws attention to various Polaroids taken of Buffalo Bill in the company of strippers; these are visible in Gumb's basement in the film.